Cardiovascular Flashcards

Question

Atropine

Answer 1

Anticholinergic Naturally occurring tertiary amine Ester of tropic acid + tropine Racemic mixture - only L-isomer active Dose - 200-600mcg bolus, 3mg needed for total vagal blockade PK - A - <25 PO bioavailability - D - 50% protein bound - crosses placenta and BBB. TTPE 204mins, Duration 30-60mins - M - extensive metabolism by hepatic and tissue esterases, hydrolysed to tropic + tropic acid - E - renal excretion of metabolites, minimal unchanged. T1/2 = 150mins

Answer 2

Anticholinergic Synthetic quaternary amine Mandelic acid + tropine No isomerism Dose - 200-400mcg, 2.5mg neostigmine/500mcg glyco Physically incompatible with thio, diaz PK - A - PO bioavailability <5% - D - onset 3-9mins, rapid redistribution with 95% leaving plasma after 5mins, duration - antivagal for 3hrs, antisialagogue for 6hrs - M - minimal metabolism - E - 85% excreted unchanged in urine. T1/2 75mins

Answer 3

Anticholinergic Naturally occurring tertiary amine Ester of tropic acid + scopine Racemic mixture - only L-isomer active Hyoscine butyl bromide (buscopan) - does not cross BBB, does not cause sedation or central anti-emetic effects Hyoscine hydro-bromide (scopolamine) - crosses BBB Uses - antispasmodic, motion sickness Dose - butylbromide 10-20mg PK - A - scopolamine used as transdermal patch, PO bioavailability 10%, well absorbed SC or IM - D - faster onset than atropine, DoA 2hrs - M - extensive metabolism by hepatic esterases and in tissues, metabolised to scopine + tropic acid - E - renal excretion of metabolites, T1/2 2.5hrs

Answer 4

Non selective a1 + a2 antagonists- phentolamine + phenyxoybenzamine Phentolamine - a1 >a2 (3:1) - Used for pheochromocytoma - 10mg/ml (dilute in 20ml = 0.5mg/ml) - 1ml bolus - Onset 1-2mins, DoA 5-20mins - Hepatic metabolism - Essential anti-metaraminol - a1 - arterial vasodilation (↓SVR + BP), ↓PVR - a2 - presynaptic ↑NA, ↑HR - ↑CO - reflex tachycardia + ↑contractility triggered by baroreceptor reflex to ↓BP (a1) => ↑central SNS outflow, ↑NA release (a2) Phenoxybenzamine - Irreversible a blocker (a1 > a2) - covalent bond - Used for phaeochromocytoma - Long acting - Inhibition of presynaptic reuptake of NA - Corrects HTN and vasoconstriction - Reduces intravascular volume deficit - May cause sedation Selective antagonists a1 - Prazosin a2 - Yohimbine Prazosin - Used for HTN, BPH, Raynaud's - Arterial vasodilation and venodilation -> ↓SVR -> ↓BP. ↓Preload - 1st dose postural hypotension - Relaxes prostate and ureteric SM -> Improves urine flow - Hepatic metabolism, T1/2 7hrs - Dose 0.5-5mg Yohimbine - Used for impotence - Adverse effects - tachycardia, HTN, insomnia, anxiety, hallucinations

Answer 5

Phenylethylamines - a-methyldopa, NA Imidazolines - clonidine, moxonidine, dexmed Receptor subtypes - a2a - mediates sedation, hypnosis, analgesis, neuroprotection, sympatholysis => Gi protein associated - ↓cAMP - a2b - mediates vasoconstriction, anti-shivering, analgesia - a2c - learning, stress response

Answer 6

MoA - Antagonise B adrenergic receptor - GsPCR -> ↓cAMP -> ↓PKA activation -> ↓phosphorylation of intracellular targets - Cardiac pacemaker cells - ↓HCN channel activation -> ↓slope phase 4 -> ↓HR - Ventricular myocyte -> ↓phosphyrolation of => Membrane L-Ca and SR ryanodine sensitive Ca channel (↓Ca influx) => Myosin (↓rate at which x-bridge cycling occurs) => Trop I and phospholamban (↓relaxation rate) Classification - receptor selectivity - Non-selective for B1 + B2 - propranolol, timolol, sotalol, carvedilol - Cardio-selective for B1 - metoprolol, atenolol, esmolol - Mixed a + B - labetalol (B non-selective, a1 selective, B >>a1) Classification - intrinsic sympathomimetic - Partial B agonist activity = intrinsic sympathomimetic activity. Submaximal response despite maximal occupancy of B receptors. Low level circulating catecholamines -> agonist effects. High levels -> antagonist - Present - Pindolol, acebutolol, timolol, labetalol at B2 - Absent - propranolol, metoprolol, atenolol, esmolol, sotalol Lipid solubility - High (cross BBB) - propranolol, metoprolol, labetalol, carvedilol, timolol, pindolol - Low (doesn't cross BBB) - esmolol, atenolol

Answer 7

CNS - More lipid soluble BB (propranolol, metoprolol) => Hallucinations, depression, nightmares - MAC-sparing effects - Mask effect of inadequate anaesthesia - ↓IOP (↓production of aqueous humour) CVS - Negative inotropic effect (↓myocardial O2 demand) - Negative chronotropic ( ↓SAN automaticity, ↓AVN conductivity, ↓HR, AV block, ↑myocardial O2 supply) - Class II anti-arrhythmic - ↓BP - Rebound HTN after abrupt discontinuation - May precipitate acute cardiac failure - Exacerbation of PVD (B2) - Exacerbation of Raynaud's (B2) - ↓HTN response to intubation + extubation - Cardioprotective - ↓stress on atherosclerotic plaques, ↓cardiac cell apoptosis and necrosis, ↓plt aggregation, ↓B-receptor down regulation RS - Bronchospasm (B2) - caution in asthma Metabolic - Glucose - interference with glycogenolysis, obtund normal blood sugar response to ↓BSL, mask sx of ↓BSL - Lipids - ↑triglycerides, ↓HDL - ↓Renin release at juxtaglomerular apparatus (B1) -> ↓AT-II and its effects - Hyperkalaemia GIT - Dry mouth Other - Esmolol - vein irritation and tissue necrosis after extravasation Caution in - Severe LV failure - AV conduction delay - Asthma, COPD - Diabetes - PVD - reflex vasoconstriction

Answer 8

Racemic mixture Dose 1-2mg Q2-5mins PK - A - >95% PO absorption, but only 50% bioavailable - D - IV onset 1-2mins, duration 5-8hrs. High lipid solubility - high lipid solubility, crosses BBB and breast milk. 15% protein bound, VD 5.5L/kg - M - hepatic -> alpha-hydroxymetorprolol (10% activity). CYP2D6 O-demethylation > CYP3A4. CYP2D6 polymorphism (i.e slow metabolisers) - E - renal excretion as metabolites, T1/2 3-7hrs PD - Selective B1 (cardiac) - No intrinsic sympathomimetic activity - Weak membrane stability activity

Answer 9

10mg/ml solution Dose 0.5mg/kg bolus, infusion 50-150mcg/kg/min PK - D - onset 6-10mins, offset 20mins, 55% protein bound, VD 3.5L/kg. High lipid solubility. Crosses placenta poorly. - M - hydrolysis by red cell esterases to methanol and a primary acid metabolite (metabolite has minimal weak B antagonist activity) - E - 70-80% in urine as metabolite, T1/2 10mins PD - Selective B1 (cardiac), at high doses may have B2 - Obtunds CVS response to intubation and sternotomy

Answer 10

Mixture of 4 isomer - R-R isomer has B activity - S-isomer has a activity PK - A - 70% PO absorption, with 25% bioavailability, significant first pass metabolism - D - highly lipid soluble, crosses BBB. 50% protein bound, variable VD 2-15L/kg - M - extensively metabolised in liver to inactive conjugates - E - renal excretion of metabolites. T1/2 3-8hrs PD - Mixed a + B antagonist (a1, B1, B2)- has intrinsic sympathomimetic activity at B2 (may cause vasodilation at vascular SM directly), ↓SVR - B-non selective - B>>a (7:1 IV, 3:1 PO) - Safe in pregnancy - Alpha adverse reactions more common than B - nasal congestion, dizziness

Answer 11

Racemic mixture - S-isomer responsible for most effects - R-isomer prevents peripheral conversion of T4 to T3 Dose = 1-2mg bolus Q2mina PK - A - >90% absorbed, with 30% bioavailability - D - High lipid solubility. 90% protein bound, VD 3.5L/kg - M - hepatic oxidative deamination then dealkylation or glucuronidation. Active 4-OH metabolite - E - Renal elimination, T1/2 3-5hrs PD - Non-selective B1 + B2 - also timolol

Answer 12

Non-selective blocker Class II + III antiarrhythmic- blocks B-receptors and K+ ↑refractory period Racemic mixture; L - class II + III, D - class III Dose - PO 160-320mg, IV 0.5-1.5mg/kg A - PO bioavailability 75-90% D - Low lipid solubility M - not metabolised E - renal excretion, T1/2 12hrs S/E - B-blocker effects - Torsade de point - ↑risk with high dose, bradycardia, antiarrhythmics, low Mg + K

Answer 13

Classification - Sulfhydryl-containing - captopril - Dicarboxylate-containing - enalapril, ramipril, perindopril, lisinopril - Phosphate-containing - fosinopril Indications - HTN, IHD, CCF MoA - Competitive ACE inhibitor -> ↓conversion of AT-I to AT-II -> ↓effects of AT-II - ↓Breakdown of bradykinin CVS - Arterial vasodilation - ↓SVR + BP (CO may ↑ due to ↓after load) - HR and baroreceptor reflex unaffected Renal - If poor renal perfusion (renal artery stenosis, hypovolaemia) - impaired efferent arteriole vasoconstriction, ↓GFR, renal impairment - Hyeprkalaeima (↓aldosterone release) - ↑RBF and may cause natriuresis Other - Dry cough - bradykinin mediated - Angioedema - Agranulocytosis and thrombocytopenia - Rash - Hypotension, dizziness, fatigue, GI upset - 1st dose hypotension Anaesthesia - Hypotensive effect additive - ↑Intra and post-op hypotension if not withheld - ↑risk of renal failure/ AKI due to hypo perfusion under anaesthesia - esp if concomitant use of NSAIDs

Answer 14

E.g losartan, candesartan Indications - HTN, IHD, CCF MoA - Specific ATII (AT1) receptor antagonist - Does not block AT2 and ACE - Does not ↑bradykinin level Effects - Similar to those of ACEi - No dry cough - No angioedema Angiotensin II - MoA - two subtype of AT-II receptors (GPCRs) => AT1 + AT2 => AT-II has greater affinity for AT1 receptors Effects - Potent vasoconstriction - ↑ADH - ↑Aldosterone - ↑Thirst - ↓Renin - ↓GFR

Answer 15

Dose 5-10mg Q5min to effect- adult dose 20-40mg IV MoA - Direct action on vascular SM => Hyperpolarisation via opening of K channels => ↓intracellular Ca in vascular SM via inhibition of IP3 => Activation of guanylate cyclase via NO PK - A - bioavailability ~15-30% - D - onset within 15mins, highly protein bound, high VD 4L/kg, crosses placenta -> fatal tachycardia - M - acetylation and oxidation with subsequent conjugation. Genetic polymorphisms -> fast and slow acetylators - E - 50-90% excreted in urine, T1/2 1-3hrs CVS - ↓SVR - arterial vasodilation - ↑CO due to ↓after load - Reflex tachycardia - can be used with B-blockers to prevent - ↑CBF - ↑RBF secondary to CO Other - N+V - Oedema due to Na retention and ↓UO - ↑Plasma renin - SLE-like syndrome with high doses - higher in females - typically with chronic use in slow acetylators - Peripheral neuropathy/ blood dyscrasia - rare

Answer 16

Classification - Phenyl-alkylamines - verapamil - Dihydropyridine - nifedipine, amlodipine, nimodipine - Benzo-thiapines - diltiazem Indications - HTN, IHD, Raynaud's, SVT/AF/ Aflutter, tocolysis MoA - Competitive voltage gated L-type Ca2+ channel antagonism -> ↓Ca influx -> ↓intracellular Ca -> ↓SAN automaticity, ↓AVN conductivity, vasodilation, some negative inotropic effect PK - Well absorbed but limit bioavailability - Lipid soluble, high VD (2-4L/kg), high protein binding - High hepatic metabolism with relatively short T1/2 CNS - Arterial vasodilation -> ↓SVR + BP, ↑CO (due to ↑HR + ↓afterload), ↑coronary BF, ↑cerebral BF -> ↑ICP -> headache - Min venous vasodilation - Reflex tachycardia - ↓myocardial contractility -> may precipitate cardiac failure RS - ↓HPV Other - Tocolysis - Peripheral oedema Drug interaction - May potentiate effect of NDMR - Additive negative inotropic effects with volatiles -> profound drop in CO (incr risk of sinus pause, ↓MAC) - Dantrolene and verapamil -> hyperkalaemia

Answer 17

Inorganic gas Used as selective pulm vasodilator in pulm HTN MoA - Produced in vivo by NO synthase from L-arginine and O2 - requires NADP - cGMP - diffuses to vascular SM layer and stimulates guanylate cyclase, ↑cGMP which activates a phosphorylation cascade -> SM relaxation + vasodilation. May also activate K channels hyperpolarising cell and ↓Ca entry PK - A - inhalation route (5-20ppm dose), continuous flow system ↓bolus effect (also minimises NO2 formation - ↓time for NO + O2 to mix) - M - NO combines with oxyHb that is 60-100% saturated producing MetHb and nitrate; readily reacts with metal ions (Fe2+) in proteins and enzymes. Reacts with harm moiety in guanylate cyclase to ↑cGMP. - During first 8hrs of admin MetHb ↑ - E- T1/2 <5s, nitrate eliminate via urine CNS - ↑CBF and may act as NT within ANS + CNS - role in learning, memory, analgesia, may ↑MAC CVS - Potent vasodilation - inhalation ensures selective pulm vasodilation due to rapid metabolism (avidly binds Hb and is inactivated prior to reaching systemic) - Inhibits platelet aggregation - anti-thrombotic - Anti-atherogenic - ↓proliferation of SM, expression of adhesion molecules, permeability to lipoproteins RS - Improves V/Q matching - Abrupt cessation -> hyperaemia due to down regulation of endogenous production Immune - Macrophages use it to inhibit bacterial Fe-containing enzymes -> cell lysis - Role in COX-2 activation and PG production Toxicity - MetHb - ↓O2 carrying capacity - ↓platelet aggregation and adhesion -> bleeding - Formation of NO2 if high O2 -> pulm toxicity, oedema, pneumonitis

Answer 18

Light brown solution when reconstituted with 5% dextrose - Dark brown after exposure to light - liberation of cyanide ion (light sensitive breakdown) - Fe2+ surrounded by 5xCN- and 1x NO Clinical use - HTN crisis, LV failure Dose - 0.5-6mcg/kg/min titrated to response MoA - Interacts with sulfhydryl groups in SM cell membrane stabilising membrane and preventing Ca influx - Mediates effects via NO => Reacts with oxyHb to form NO, metHb and 5 CN- => Tolerance does not occur but MetHb does => Activates guanylate cyclase ↑cGMP and ↓intracellular Ca -> vasodilation A - Not absorbed from GIT D - onset immediate, TTPE 1-2mins, DoA 1-10mins. Confined to plasma + ECF M - reacts with oxyHb in RBC to form NO, 5CN-, MetHb (MetHb + CN- -> cyano-metHb). Remaining cyanide converted in liver and kidneys to thiocyanate (100x less toxic than CN-, mostly excreted in urine) E - T1/2 2mins, thiocyanate T1/2 2 days CVS - Arterial vasodilation - equal arterial + venous => ↓SVR + BP => ↑CBF + ICP - may cause steal phenomenon => ↓wall tension => Reflex ↑ renin release - Venodilation - ↓VR -> ↓preload - ↓Myocardial O2 consumption due to ↓preload and afterload - Reflex tachycardia - ↑CO in failing heart (↓preload + ↓afterload) RS - ↓HPV -> ↑shunt => ↓PaO2 - ↓PVR Other - MetHb - ↓LOS tone - May cause ileus - Metabolic acidosis may occur - ↑cerebral BF - Uterine relaxation Sodium nitroprusside toxicity Cyanide ions (CN-) - Major risk - toxic plasma levels >8ug/ml - Free CN- ions can bind cytochrome oxidase -> uncoupling of oxidative phosphorylation -> impaired aerobic metabolism -> tissues unable to utilise O2 - hypoxia and lactic acidosis with ↑PvO2 MetHb + CN- - Cyano-methaemoglobin (does not bind O2) Excessive production of NO -> arterial vasodilation -> hypotension Thiocyanate - CNS toxicity - hyperreflexia, confusion, seizure, coma Signs - Tachyphylaxis - Hypotension - Tachycardia - Arrhythmias - Hyperventilation - Sweating - Metabolic acidosis Management - Stop infusion - Supplement O2 - Dicobalt edetate (chelate CN- ions) - Sodium thiosulphate (converts CN- to thiocyanate) - Nitrates - convert oxyHb to metHb, metHb has higher affinity to CN- than cytochrome oxidase - Methylene blue - reducing agent, reduces metHb to Hb - Vit B12 - forms cyanocobalamin

Answer 19

Organic nitrate - ester of nitric acid Clinical uses - angina, LV failure secondary to MI, peri-op BP control Dose - 300-600mcg tablets, 400mcg SL spray, 10-400mcg/min IV infusion - ISMN is a PO bioavailable form with same MoA MoA - Prodrug rapidly metabolised to NO - NO -> ↑cGMP -> ↓Ca PK - A - rapid absorption from SL mucosa and GIT. Minimal PO bioavailability, extensive first pass metabolism - D - peak effect 2mins IV, 15-30mins mucosal - M - rapid hepatic and RBC hydrolysis to glyceryl dinitrate then nitrite then NO - E - 80% excreted in urine. T1/2 1-3mins CVS - Venodilation => ↓VR + preload => ↓LVEDP + wall tension - Arterial vasodilation at higher doses ( ↑coronary BF - redistributes flow to subendocardium, auto regulation maintained, attenuates coronary vasospasm => ↑cerebral BF + ICP -> headaceh => ↓SVR at high doses - ↓myocardial O2 consumption - due to ↓preload and afterload => Primary mechanism of relieving angina, also alleviated coronary vasospasm - Reflex tachycardia - ↑CO in failing heart RS - Bronchodilation - ↓PVR - ↓HPV -> ↑shunt -> ↓PaO2 Other - ↓uterine smooth muscle tone - tocolytic - Relaxation of GIT sphincters - Inhibit plt aggregation - MetHb after prolonged use - Cerebral vasodilation -> headache - Tolerance - depletion of sulfhydryl groups in vascular SM

Answer 20

Hydralazine, labetalol - Low maternal:fetus ratio despite lipid solubility a-methyldopa, prazosin, nifedipine Avoid - ACEi/ARB - teratogenic 1st trimester, later cause fetal growth restriction and oligohydramnios, incr still birth, renal failure - DHP (CCBs) - 1str trimester teratogens - Diuretics - reduce normal plasma volume expansion of pregnancy, electrolyte derangement - B-blocker without ISA - ↓uterine blood flow, atenolol causes FGR - GTN, nitroprusside (risk of CN toxicity and MetHb in foetus)

Answer 21

Demand = 30ml/min (directly proportional to HR, contractility, wall tension) Supply = 250ml/min (5% CO), O2 content of blood (Hb, SaO2), coronary flow Myocardial O2 extraction - 60% (very high, near max) - O2 supply can only be incr by incr flow Drugs used to manage myocardial ischaemia/ infarction: Nitrates - Venodilation -> ↓myocardial O2 demand (↓preload, ↓LVEDP + wall tension) - ↑O2 supply - coronary vasodilation and flow BB - ↑O2 supply - negative chronotropic effect ↑LV O2 delivery - ↓demand - negative inotropic effect CCB - ↑supply - arterial vasodilation ↑Coronary BF - ↓demand - vasodilation ↓afterload and wall tension, negative inotropic effect ACEi/ARB - ↑supply - ↑CBF by vasodialtion - ↓demand - arterial vasodilation ↓afterload and wall tension, venous vasodilation ↓VR/ preload - Activation of LDL receptors - ↓plasma LDL - plaque stabilisation Anti-platelets, anticoagulants + fibrinolytic

Answer 22

HFrEF - Sx with or without signs of HF - AND LVEF <50% HFpEF - Sx with or without signs of HF - AND LVEF >50% - AND objective evidence of relevant structural heart disease (LV hypertrophy, LA enlargement) and/or diastolic dysfunction with high filling pressures Sympathomimetics - Used for incr contractility in acute failure, i.e dobutamine PDEi - Inodilators (milrinone) useful for short term management of CCG - Incr mortality with long term use Digoxin - Used for positive inotropy with negative chronotropy - Improves supply/ demand balance Diuretics - Remove volume and ↓prelod - Spironolactone ↓mortality from chronic CCF - Frusemide agent of choice ACEi - ↓afterload and positive effect on cardiac remodelling Nitrates - ↓preload B-blockers - Improve mortality - Prevent downregulation/ desensitisation of adrenergic receptors from chronic high sympathetic stimulus - Carvedilol - non selective B and a1 blocker improves mortality Neprilysin inhibitor - Sacubitril - Incr bradykinin, natriuretic peptides - ↓Na+, H2O retention - ↓remodelling

Answer 23

e.g hydrochlorothiazide, chlorthalidone Moderately potent Site of action - early segment of DCT MoA - Block Na/Cl co-transporter in early segment of DCT - ↓Na + Cl reabsorption - ↑H2O excretion CVS - ↓BP by ↓plasma volume - Arterial vasodilation -> ↓SVR Renal/ electrolytes - ↓RBF -> may ↓GFR - ↓K+ - more Na reaches CD -> ↑Na/K exchange by Na/K ATPase in principal cells -> ↑K+ in CD -> ↑exchange of K for H by K/H pump in type A intercalated cells -> loss of H -> hypokalaemic, hypochloraemic metabolic alkalosis - ↓Na+ - ↓Cl- - ↓Mg2+ - ↑Ca - Hyperuricaemia - uric acid competes with thiazides for the same secreting mechanism, ↓uric acid excretion - ↑BSL - ↓insulin -> ↓glycogenesis, ↑glycogenolysis Other - ↑plasma cholesterol and triglyceride levels - Blood dyscrasia

Answer 24

- Thiazides - hydrochlorthiazide - Loop - frusemide - K-sparing - amiloride - Aldosterone antagonist - spironolactone - Osmotic diuretics - mannitol - Carbonic anhydrase inhibitor - acetazolamide

Answer 25

e.g Frusemide, bumetanide Potent diuresis Site of action - thick ascending LoH MoA - Block Na/K/2Cl cotransporter in thick ascending LoH -> ↓Na + Cl reabsorption -> impaired counter current multiplier mechanism -> ↓generation of hypertonic medulla -> ↓absorption of H2O in CD -> hypotonic/ isotonic urine produced - ↓K+ reabsorption - Interferes with tubuloglomerular feedback - also Na/K/2Cl co-transporter Frusemide - Sulphonamide derivative - Clear solution must be protected from light PK - A - PO bioavailability 65%, starts a few mins post IV admin, lasts 2hrs - D - highly protein bound to albumin - M - renal to a glucuronide - E - 80% excreted unchanged in urine, T1/2 45-90mins CVS - ↓BP - ↓plasma volume (BP does not ↓ if fluid overloaded), arterial vasodilation -> ↓SVR (unclear mechanism) Renal/ electrolytes - ↑RBF (cf. thiazides) - ↓K+, ↓Na+, ↓Cl- - ↓Ca2+ (cf thiazides) - Hyperuricaemia - ↓uric acid excretion - ↓Renal O2 consumption - may be protective in iscahemia Other - ↑BSL -> ↓insulin -> ↓glycogenesis, ↑glycogenolysis - ↑ cholesterol + triglycerides - Metabolic alkalosis - ↑H+ excretion in distal tubules - Deafness - esp if co-administered with aminoglycoside - ↓cAMP in presynaptic neutron potentiating NMB

Answer 26

E.g Amiloride Weak potency Site of action - DCT + CD MoA - Directly block Na/K exchanger => ↓Na reabsorption -> ↑diuresis => ↓K secretion -> ↑K+ PK - Not metabolised by liver - 50% excreted unchanged by kidneys, 40% in faeces

Answer 27

E.g spironolactone Weak potency Site of action - CCD MoA - Intracellular aldosterone receptor antagonist => ↓Na + H2O reabsorption -> ↑diuresis => ↓K secretion -> hyperkalaemia => Antagonism of the effect of aldosterone on arteriolar SM -> ↓BP Spironolactone PK - Partially absorbed ~65% - Undergoes enterohepatic recirculation - T1/2 1.6hrs CVS - Antagonism of aldosterone effect on vascular SM -> ↓SVR + ↓BP Other - Cross reactivity with other receptors - androgen receptor antagonist (e.g gynaecomastia) - Progesterone receptor agonist -> menstrual irregularities Aldosterone - Acts in renal CCD to ↑Na reabsorption, K+ secretion by principle cells, and H+ secretion by type A cells

Answer 28

Monosaccharide derived from mannose Clinical uses - ↓ICP, diuresis post renal transplant, bowel prep 10% and 20% solution (1100mOsm/L for 20%) MoA - Two phases => Volume expansion (VE) - ↑plasma volume, ↑plasma osmolality -> contraction of ICF => Volume contraction (VC) - osmotic diuresis, ↓plasma volume - Volume expansion => Hypertonic compared to plasma => ↑plasma osmolality - movement of fluid from interstitial to intracellular spaces => ↑plasma volume + ↓intracellular volume => Activation of osmotic receptors -> ↑ADH secretion and thirst -> early volume retention - Volume contraction => Freely filtered but not reabsorbed or secreted => ↑osmolarity of the tubular fluid/filtrate => ↓passive water reabsorption down Na gradient - impairs passive reabsorption of solutes requiring concentration gradient from water reabsorption (glucose, etc), water loss in excess of electrolytes => ↑renal plasma renal flow rate - washes out medullary conc gradient -> ↓ability to produce concentrated urine => ↑urine flow rate - osmotic drag - Diuresis => Osmotic effect - diuresis limited by compensatory ↑ADH. Hyponatraemia and hypokalaemia (↑Na/K exchange in distal nephron due to high flow rate). Urea may ↑ => ↑RBF => ↓Renin secretion PK - D - does not freely cross BBB, does not cross cell membranes (large molecules). Acts within a few mins and last 1-4hrs. Biphasic distribution to plasma and ECF - M - not metabolised - E - excreted unchanged in urine. T1/2 70mins CNS - ↓CSF/ ICP - ↓rate of CSF formation - ↑plasma osmolarity ↓ultra filtrate - Withdraws brain ECF across the BBB into the plasma - if BBB disrupted crosses and is thus ineffective - Preserved CBF in pt with intact autoregulation CVS - ↑CO + BP initially in VE phase - Volume contraction -> ↓preload and ↓CO, can lead to impaired perfusion if severe Adverse - Circulatory overload - pulmonary oedema (esp in CCF), compensatory ↑ANP: ↑RA stretch -> ↑release -> diuresis, natriuresis - Rebound ↑ICP - production of idiogenic osmoles, hence ↑risk of cerebral oedema - Allergy rare - Irritant to tissues and veins - Possible toxic effects on DCT + CD - ↑osmolarity >320mOsm/L if >3g/kg/day given - Dehydration and hypovolaemia - diuresis and volume loss - Electrolyte disturbances

Answer 29

e.g acetazolamide Weak potency Site of action - PCT MoA - Carbonic anhydrase catalyses CO2 + H20 <=> H2CO3 <=> H+ + HCO3- - Non-competitive inhibition of carbonic anhydrase => ↓HCO3 reabsorption + ↓H secretion -> => Metabolic acidosis => Alkaline urine => ↓ability to exchange Na for K -> ↓Na reabsorption -> ↑diuresis

Answer 30

Class Ia - Na+ channel blockade -> mod reduction in slope of phase 0, ↑duration of refractory period, ↑duration of AP - Site of action - atria, ventricles, accessory pathways - E.g quinidine, procainamide - Uses - ventricular arrhythmia, prevention of pAF, maintain SR post conversion of AF/WPW - Advers - QT prolongation Class Ib - Na+ channel blockade -> small reduction in slope of phase 0, ↓duration of refractory period, ↓duration of AP - Site of action ventricles - E.g lignocaine, phenytoin - Uses - VF/VT (lignocaine) Class Ic - Na+ channel blockade -> pronounced reduction in the slope of phase 0, nil effect on refractory period, nil effect on duration of AP - Site of action - atria, ventricles, accessory pathways - E.g flecainide, propafenone - Uses - prevention of pAF, tachyarrhythmias with abnormal conduction, avoid in structural heart disease/ MI - can cause HF Class II - B-adrenoceptor -> no change of phase 0, ↑duration of refractory period, ↑duration of AP - Site of action - SAN, AVN - E.g propranolol, atenolol, esmolol - Uses - rate control, reduce MI mortality Class III - K+ channel blockade (Ik1) -> no change of phase 0, prolonged repolarisation phase 3, ↑↑duration of the refractory period, ↑duration of AP - Site of action - atria, ventricles, accessory pathways - E.g amiodarone, bretylium, ibutilide, sotalol (both class II + III) - Uses - WPW, VT/VF, maintain SR post AF conversion - Adverse - prolong QT Class IV - L-type Ca channel blockade -> nil change of phase 0, ↓duration of plateau phase 2, ↓duration of AP - Site of action - AVN - E.g verapamil, diltiazem - Uses - prevention of recurrent SVT, rate reduction in AF Other - Adenosine - activates adenosine receptors - Digoxin - Na pump inhibitor - Mg - CCB

Answer 31

Amide LA Class IIc antiarrhythmic - Na channel blocker -> ↓rate of max depolarisation, pronounced reduction in slope 0, nil change to refractory period, nil change to duration of AP Uses - prevention pAF, tachyarrhythmia with abnormal conduction (WPW), avoid in structural heart disease/ MI - can cause HF PK - A - rapid PO absorption, 90% bioavailability - M - hepatic - E - Urine, dose reduction in renal/ hepatic impairment CVS - Well tolerated, min BP + HR effects - Negative inotrope potential Other - Visual disturbances - Liver impairment - Nausea, headache Drug interaction - Incr Cp of digoxin - Hypokalaemia reduced effect

Answer 32

Resembles thyroxine Clinical uses - SVT, VT, WPW, cardiac arrest with shockable rhythm, rate control in AF Dose - 300mg push in arrest, 150-300mg load, 15mg/kg/day subsequently, therapeutic level 0.1mcg/ml MoA - Class III anti arrhythmic - K+ channel blockade - ↓slow outward K+ current (at higher doses blocks Na + Ca inward currents), prolonged repolarisation phase 3, ↑↑duration of refractory period, ↑duration of AP - Partial antagonist of a- and b- agonists by reducing receptor number or inhibiting coupling of receptors to adenyl cyclase - Class Ia, II and IV activity in addition PK - A - variable PO bioavailability (20-80%) - D - 95% protein bound, VD up to 70L/kg - accumulated in muscles and fat (long duration of action + T1/2), very large Vd due to tissue accumulation (requires prolonged loading). IV onset 5mins, IV duration 30mins for bolus. High lipid solubility. - M - extensive hepatic metabolic -> active metabolite (anti arrhythmic properties) - E - Predominantly bile, but also through lacrimal glands and skin. T/12 15-140days CVS - Slows SR, prolongs AV conduction - prolongs AP and RP (primarily K channel blockade), no change to phase 0, prolonged repolarisation phase 3 - Prolonged QT interval - Rapid infusion -> bradycardia + hypotension (B and a blockade -> vasodilation + ↓CO) RS - Pulm fibrosis/ ILD (risk factors - prolonged therapy, high cumulative dose, ↑age, pre-existing pulm disease, ↑FiO2) Other - Hypothyroidism >> hyperthyroidism (inhibit T3 production) - Hepatitis - GI upset - Corneal micro-deposits - Peripheral neuropathies - Photosensitivity - Blue-grey discolouration of skin Drug interaction - Drugs that prolong QTc (e.g droperidol, TCA, phenothiazines) - Drugs that ↓AVN conductivity (e.g B-blockers, CCB) - Potentiates effect of highly protein bound drugs by displacement (e.g warfarin, phenytoin, digoxin)

Answer 33

Synthetic papaverine derivative Calcium channel blocker Clinical uses - paroxysmal SVT, AF/ Aflutter rate control MoA - Class IV antiarrhythmic - Competitive antagonist of L-type Ca channels - ↓Ca influx into cardiac and vascular SM - ↓slow Ca depolarisation - ↓HR - slows conduction through SAN + AVN - No change to phase 0, ↓duration of plateau phase 2 + AP PK - A - complete PO absorption, 20% bioavailability due to extensive first pass metabolism - D - 90% protein bound - M - hepatic, metabolites have some activity - E - 70% in urine, T1/2 5hrs CVS - ↓AVN conduction + HR - ↓SVR - Potent coronary vasodilator - Negative dromotropic and inotropic effects enhanced by acidosis Adverse - Flushing, dizziness - Heart block - HF if impaired LV function - VT/ VF in WPW Drug interactions - Synergy with volatiles on negative isotropy and conduction (dromotropy)

Answer 34

- Glycoside - extracted from leaves of digitalis - Steroid cyclopentanopenanthrene nucleus with => Glycone portion (inactive) -> sugar that fixes drug to cardiac muscle => Aglycone portion (active) -> exerts drugs activity - Clinical uses - AF/ Aflutter, cardiac failure - Doses - loading 10-20mcg/kg Q6hrly, maintenance 10-20mcg/kg/day in divide doses MoA - Direct action => Inhibits cardiac Na/K ATPase -> ↑intracellular Na, ↓K -> ↓Ca extrusion by Na/Ca exchanger due to ↓Na gradient -> ↑intracellular Ca -> positive inotropic effect => ↓intracellular K hyperpolarises cell and slows AV conduction and automaticity of pacemaker cells -> ↑AVN refractory period - Indirect action => ↑release of Ach at cardiac MAChR - vagotonic => ↓SAN automaticity and AVN conductivity => Negative chronotropic effect - rate control PK - A - variable PO absorption, 60-80% bioavailability - D - 25% protein bound, VD 5-10L/kg (very large), peak effect at 2hrs - M - min hepatic metabolism - E - renal, T1/2 35hrs, up to 5days with renal impairment ECG changes - Therapeutic - down sloping ST depression, QT shortening, flattened, inverted or biphasic T-waves, slight prolongation in PR, presence of U waves Digoxin Toxicity - Low therapeutic index => Therapeutic plasma level 1-2ng/ml => Toxic plasma levels >2.5ng/ml - Incr automaticity, Decr AVN conduction, sinus brady, PVCs, AF, AV block, VT Risk factors - Hypokalaemia - Hypercalcaemia - Acid base disturbances - Renal failure Cardiac toxic effects - Premature ventricular contraction - AV block - Junctional rhythm - Prolonged PR interval - Ventricular arrhythmia ECG - Incr automaticity (SVT and atrial extrasystoles) - ↓AVN conduction - Shortened PR interval - junctional rhythm - Frequent PVCs - Sinus bradycardia - AF with escape rhythm/ slow AF - AV block - VT Non-cardiac - Anorexia - N+V - Diarrhoea - Visual disturbances - Lethargy, headache, confusion, coma Tx - Gastric lavage - Correct exacerbating factors - Bradycardia - atropine, pacing - Ventricular arrhythmias - phenytoin, lignocaine - Digoxin specific Fab (Digibind) - plasma level >20ng/mL, forms inactive digoxin-Fab complex -> ceases its therapeutic effect -> renally excreted

Answer 35

- Endogenous purine nucleoside - Present in all cells - Uses - SVT due to re-entry circuits involving AVN - Contraindications - asthma, 2nd/3rd degree AV block, sick sinus syndrome - Dose - 6mg bolus then 12mg bolus if nil effect MoA - Action on SAN and AVN via adenosine A1 receptors => GiPCR -> ↓adenyl cyclase -> ↓cAMP -> opens K+ channels -> ↑K+ efflux -> hyperpolarisation -> ↓AVN conduction and prolongs refractory period -> negative chronotropic effect PK - Rapid metabolism by adenosine deaminase or phosphorylation to AMP => Vessel wall + RBCs => Incr plasma urate - T1/2 <10s - Antagonised by methylxanthines - inhibit A1R - Potentiated by dipyridamole -> inhibit adenosine uptake CVS - Negative chronotropic effect - Incr myocardial blood flow due to coronary vasodilation - ↓PVR via endothelial A2 receptors Adverse (short-lived) - Feeling of impending doom - Bronchospasm, dyspnoea - Nausea - May cause VF if underlying AF and accessory pathway

Answer 36

- 1g = 4mmol - Uses - Torsades, refractory VT, tocolysis, pre-eclampsia, severe asthma, ↓Mg, ↓HTN response to intubation MoA - Cofactor in >300 enzymes including Na/K ATPase and oxidative phosphorylation - Membrane stabilising effect - Physiological antagonist of L-type Ca channels -> ↓SAN automaticity and ↓AVN conduction - NMDA antagonist - Ca antagonism -> SM relaxation PK - Normal = 0.7-1.1 mmol/L - Therapeutic = 2-3.5 - Drowsiness = 4 - Absent patella reflex = 5 - Heart block + resp paralysis = 7.5 - Cardiac arrest >12 - Very high TI Effects - Vasodilation - Antiarrhythmic - Bronchodilation - Tocolysis - Sedation - ↓Platelet aggregation - Prolongs effect of NDMR

Answer 37

Catecholamines: A catechol ring - A benzene ring with two hydroxyl groups in the 3 and 4 position. - Losing one hydroxyl group Increases lipid solubility and decreases the potency 10-fold Prevents metabolism by COMT, prolonging duration of action - Losing both hydroxyl groups decreases the potency 100-fold - Changing the hydroxyl groups to the 3 and 5 position increases beta-2 selectivity when there is also a large substitution present on the amine group An ethylamine tail -Beta carbon The first carbon. Adding a hydroxyl group decreases lipid solubility and CNS penetration Adding any group increases alpha and beta selectivity -Alpha carbon The second carbon. Adding a group prevents metabolism by MAO, prolonging duration of action Methylation increases indirect activity - Amine group The terminal nitrogen. Addition of a methyl group generally increases beta selectivity As the chain length increases, so does the beta selectivity.

Answer 38

A wave (atrium) - RA contraction - Correlates with P-wave on ECG - Disappears with AF C wave (cusp) - Cusp of TV protruding back through atrium, as RV begins to contract - Correlates with the end of QRS complex X descent - Movement of the RV, which descends as it contracts - Downward movement decreases the pressure in the RA. At this stage there is also diastolic relaxation, which further decreases RAP - Happens before T-wave V wave - As blood fills the RA, hits TV and this is the back pressure wave - Happens after the T-wave - Also gives an impression of tricuspid competence - Huge V wave suggests TR, as it represents blood flowing back out of the contracting RV; in this situation the V wave would be the most prominent wave and would reach RV systolic pressure (~30mmHg) Y descent - Pressure decrease caused by the TV opening in early ventricular diastole - Happens before P-wave - Loss of y-descent suggests tamponade; it means there is restriction to RV filling